The objective of this proposal is the understanding of cellular mechanisms associated with the progression of diabetic nephropathy. Diabetic nephropathy is the single largest cause of end-stage renal failure in the United States. The disease is believed to be triggered by hyperglycemia in diabetes mellitus, Previous studies by others and us have show that increased expression of cytokines and growth factors play an important role in the development of kidney disease. The mitogen- activated protein kinase (MAP kinase) family members are involved in the activation of cytokines and growth factors in renal cells exposed to high glucose, but also participate in the subsequent signal transduction of these cytokines and growth factors to mediate further cellular changes. Inhibition of a MAP kinase family member, p38, by a selective inhibitor dramatically suppressed the progression of diabetic nephropathy in a rat model (streptozotocin-induced diabetes), and activation of p38 significantly accelerated the development of diabetic nephropathy. In this application, we propose to carry out studies designed to determine the function of each MAP kinase family member in diabetic nephropathy. Specifically, we will address the role of these MAP kinases in high glucose-induced gene expression and in growth factor- and cytokine- induced renal cell activation, utilizing biochemical, molecular biological, and immunological approaches. In vivo experiments will be performed to confirm the results obtained in the in vitro studies and to develop a better understanding to the role of MAP kinases in various stages of the pathogenesis of diabetic nephropathy. Insights gained in the proposed studies will lead to the development of new therapeutic strategies to this life-threatening disease.